The overall goal of this project will continue to be the investigation of physiological mechanisms regulating airway reactivity under two conditions: (1) in vivo antigen-induced hypersensitivity, and (2) after exsanguination. Based on our previously reported observations and additional preliminary data, six hypotheses may be postulated; the aims are to test these hypotheses. This proposal is designed to carry out the aims as follows. (1) The relationship between the nonadrenergic noncholinergic (NANC) inhibitory system and antigen-induced bronchoconstriction will be examined. In pilot studies, oxyhemoglobin has been found to suppress the NANC relaxation in the guinea pig trachea in vitro, and to enhance airway spasm during antigen challenge in vivo. More studies will be performed to establish and quantitate this relationship. (2) Substance P depletion has been shown by others to desensitize airways. We will explore whether depletion of substance P can also reduce bronchial hyperreactivity following antigen challenge. (3) The importance of leukotrienes (LT, SRS-A) which are postulated mediators of antigen-induced airway constriction, will be studied by enhancement or inhibition of LT function during antigen-induced hypersensitivity. (4) Characteristics of the postmortem bronchoconstriction (a type of non-immunologically induced bronchial hyperreactivity) that we have been studying in the guinea pig lung will be further defined in terms of similarity to antigen-induced airway constriction, relationship to substance P, and sites of airway spasm.